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Disturbed Prefrontal Cortex Activity in the Absence of Schizophrenia-Like Behavioral Dysfunction in Arc/Arg3.1 Deficient Mice

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Disturbed Prefrontal Cortex Activity in the Absence of Schizophrenia-Like Behavioral Dysfunction in Arc/Arg3.1 Deficient Mice The Journal of Neuroscience, October 9, 2019 • 39(41):8149–8163 • 8149 Behavioral/Cognitive Disturbed Prefrontal Cortex Activity in the Absence of Schizophrenia-Like Behavioral Dysfunction in Arc/Arg3.1 Deficient Mice X Xiaoyan Gao,1 Jasper Grendel,1 Mary Muhia,2 Sergio Castro-Gomez,1 Ute Su¨sens,1 XDirk Isbrandt,3,4,5 Matthias Kneussel,2 XDietmar Kuhl,1 and XOra Ohana1 1Institute for Molecular and Cellular Cognition, 2Institute for Molecular Neurogenetics, 3Experimental Neuropediatrics, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg–Eppendorf, 20251 Hamburg, Germany, 4Institute for Molecular and Behavioral Neuroscience, University of Cologne, 50937 Cologne, Germany, and 5Experimental Neurophysiology, German Center for Neurodegenerative Diseases, 53175 Bonn, Germany Arc/Arg3.1, an activity regulated immediate early gene, is essential for learning and memory, synaptic plasticity, and maturation of neural networks. It has also been implicated in several neurodevelopmental disorders, including schizophrenia. Here, we used male and female constitutive and conditional Arc/Arg3.1 knock-out (KO) mice to investigate the causal relationship between Arc/Arg3.1 deletion and schizophrenia-linked neurophysiological and behavioral phenotypes. Using in vivo local field potential recordings, we observed damp- ened oscillatory activity in the prefrontal cortex (PFC) of the KO and early conditional KO (early-cKO) mice, in which Arc/Arg3.1 was deleted perinatally. Whole-cell patch-clamp recordings from neurons in PFC slices revealed altered synaptic properties and reduced network gain in the KO mice as possible mechanisms underlying the oscillation deficits. In contrast, we measured normal oscillatory activity in the PFC of late conditional KO (late-cKO) mice, in which Arc/Arg3.1 was deleted during late postnatal development. Our data show that constitutive Arc/Arg3.1 KO mice exhibit no deficit in social engagement, working memory, sensorimotor gating, native loco- motor activity, and dopaminergic innervation. Moreover, adolescent social isolation, an environmental stressor, failed to induce deficits in sociability or sensorimotor gating in adult KO mice. Thus, genetic removal of Arc/Arg3.1 per se does not cause schizophrenia-like behavior. Prenatal or perinatal deletion of Arc/Arg3.1 alters cortical network activity, however, without overtly disrupting the balance of excitation and inhibition in the brain and not promoting schizophrenia. Misregulation of Arc/Arg3.1 rather than deletion could poten- tially tip this balance and thereby promote emergence of schizophrenia and other neuropsychiatric disorders. Key words: Arc/Arg3.1; excitation/inhibition; knock-out; local field potential; prefrontal cortex; schizophrenia Significance Statement The activity-regulated and memory-linked gene Arc/Arg3.1 has been implicated in the pathogenesis of schizophrenia, but direct evidence and a mechanistic link are still missing. The current study asks whether loss of Arc/Arg3.1 can affect brain circuitry and cause schizophrenia-like symptoms in mice. The findings demonstrate that genetic deletion of Arc/Arg3.1 before puberty alters synaptic function and prefrontal cortex activity. Although brain networks are disturbed, genetic deletion of Arc/Arg3.1 does not cause schizophrenia-like behavior, even when combined with an environmental insult. It remains to be seen whether misregula- tion of Arc/Arg3.1 might critically imbalance brain networks and lead to emergence of schizophrenia. Introduction ing delusions and hallucinations, negative symptoms, including Schizophrenia is a debilitating neuropsychiatric disease with a social withdrawal and anhedonia, and cognitive symptoms re- high penetration (1%) of the population and a strong hereditary flecting deficits in working memory and executive control (van component. Although heterogeneous, the core behaviors charac- Os and Kapur, 2009; Owen et al., 2016). The neurophysiological terizing schizophrenia are divided in positive symptoms, includ- This work was supported by the Grant “Molekulare Mechanismen der Netzwerkmodifizierung” to D.K. and O.O. from the Federal State of Hamburg, by a Grant from the Schaller-Nikolich Foundation to D.K. and O.O., by the DFG Received March 19, 2019; revised Aug. 6, 2019; accepted Aug. 29, 2019. GrantKN556/11-2(FOR2419)toM.K.X.G.wassupportedbyascholarshipfromtheChinesegovernmentawardedby Author contributions: X.G., D.K., and O.O. designed research; X.G., J.G., M.M., S.C.-G., U.S., D.I., and O.O. per- theChinaScholarshipCouncil.WethankSabineHoffmeister-UlrichforperformingCNVonCrerecombinasecarrying formed research; D.K. contributed unpublished reagents/analytic tools; X.G., J.G., M.M., S.C.-G., D.I., M.K., D.K., and mice and to Peter Soba for assistance with Imaris. Confocal images were taken in the Microscopy Imaging Facility of O.O. analyzed data; X.G., D.K., and O.O. wrote the paper. the University Medical Center Hamburg–Eppendorf with technical support from Antonio Virgilio Failla. 8150 • J. Neurosci., October 9, 2019 • 39(41):8149–8163 Gao et al. • Arc/Arg3.1 Involvement in Schizophrenia characteristics of the disease include altered brain activity pat- Arc/Arg3.1 KO mice in three benchmark tests of schizophrenia in terns and uncoordinated inter-areal communication (Lisman, rodents. Moreover, given the longstanding theory about the dys- 2012; Uhlhaas and Singer, 2015; Hunt et al., 2017). Although function of the dopamine system in schizophrenia (Toda and psychosis commonly manifests during puberty and early adult- Abi-Dargham, 2007; Howes and Kapur, 2009; Howes et al., hood, cognitive and neurophysiological phenotypes can be 2015), we examined the sensitivity to dopamine elevation and the detected earlier, which has led to the prevalent view of schizo- dopaminergic innervation of the PFC and striatum. In humans, phrenia as a neurodevelopmental disorder (Rapoport et al., 2012; schizophrenia has a high rate of comorbidity with epilepsy Birnbaum and Weinberger, 2017). This view holds that the pro- (Ma¨kikyro¨ et al., 1998; Qin et al., 2005; Clarke et al., 2012), which cess of normal brain development is interrupted by polygen- is recapitulated in several animal models of the disease (Fejgin et etic and environmental factors (van Os and Kapur, 2009; al., 2014). To investigate a possible association between Arc/ Modai and Shomron, 2016; Owen et al., 2016), which ulti- Arg3.1 deletion, epileptic activity, and schizophrenia, we per- mately alter neurotransmitter systems, brain connectivity, and formed electrocorticogram recordings from chronically implanted cognitive functions. WT and KO mice while monitoring their activity over several The activity-regulated gene Arg3.1 (Link et al., 1995), also days. Finally, we tested the interaction between Arc/Arg3.1 dele- known as Arc (Lyford et al., 1995), plays an essential role in adult tion and an environmental stressor on schizophrenia-like learning and memory and synaptic plasticity (Guzowski et al., behaviors. 2000; Plath et al., 2006; Messaoudi et al., 2007; Jakkamsetti et al., 2013; El-Boustani et al., 2018; Gao et al., 2018). Additionally, Arc/Arg3.1 also mediates forms of plasticity that are prominent Materials and Methods during development, such as homeostatic synaptic scaling Mice. Mice aged 3–5 months were kept in a vivarium with an inverted (Chowdhury et al., 2006; Shepherd et al., 2006), metabotropic 12 h light/dark cycle (08:00–20:00 dark period) in groups, under stan- Ϯ glutamate receptor-dependent long-term depression (Waung et dard housing conditions (23 1°C, 40–50% humidity; food and water al., 2008) and synapse elimination (Mikuni et al., 2013). Arc/ ad libitum). Animals were housed together in groups of 3–5 mice per cage. Mice subjected to social isolation were housed individually from Arg3.1 upregulation during early postnatal development shapes postnatal day (P)35 until the day of the experiment. Both male and hippocampal oscillatory activity and learning capacity (Gao et al., female mice were used in all experiments. All procedures were conducted 2018), likely by changing network connectivity and microarchi- in accordance with the German and European Community laws on pro- tecture. This may also explain why misregulation of Arc/Arg3.1 is tection of experimental animals and approved by the local authorities of linked to neurodevelopmental diseases, such as fragile X Syn- the City of Hamburg. Experimenters were blind to the genotype until the drome (Niere et al., 2012; Ronesi et al., 2012) and Angelman conclusion of experiments and analysis. syndrome (Greer et al., 2010; Cao et al., 2013; Mandel-Brehm et Generation of constitutive and conditional Arc/Arg3.1 KO mice. Arc/ al., 2015). Previous studies on schizophrenia patients implicated Arg3.1 KO mice were generated as previously described (Plath et al., Arc/Arg3.1 as a molecular hub in synaptic gene networks whose 2006). Along with the KO mice generation, floxed Arc/Arg3.1 mutants f/f abnormalities possibly play a significant role in the pathogenesis (Arc/Arg3.1 ) were generated in parallel and thoroughly validated for of schizophrenia (Kirov et al., 2012; Fromer et al., 2014; Purcell et use in biochemical and behavioral experiments (Gao et al., 2018). Con- ditional Arc/Arg3.1 gene ablation in the brain was accomplished by al., 2014; Ferna´ndez et al., 2017). In addition, a recent study breeding Arc/Arg3.1f/f with the Cre recombinase transgenic mice (1) (Manago` et al., 2016) reported schizophrenia-like behaviors and Tg(CaMKII␣-cre)1Gsc
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